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Article ; Online: Ling-Gui-Zhu-Gan decoction protects against doxorubicin-induced myocardial injury by downregulating ferroptosis.

Yang, Ya-Li / Zhao, Chuan-Zhi / Zhao, Chun-Chun / Wen, Zhong-Yu / Ma, Yao-Yao / Zhao, Xiao-Ni / Wang, Liang / Huang, Jin-Ling / Zhou, Peng

The Journal of pharmacy and pharmacology

2024 Volume 76, Issue 4, Page(s) 405–415

Abstract: Objective: To investigate the mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) protects against ...

Abstract	Objective: To investigate the mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) protects against doxorubicin (DOX)-induced myocardial injury. Methods: In vivo experiment, rats were divided into six groups: normal group, model group (15 mg/kg, DOX), Dex group(150 mg/kg, Dex), LGZGD-L group (2.1 g/kg), LGZGD-M group (4.2 g/kg), and LGZGD-H group (8.4 g/kg). We used HE and Masson staining to observe the histopathological changes, echocardiography to assess the cardiac function, and western blot and RT-qPCR to detect the expressions of Nrf2, GPX4, Fpn1, and Ptgs2. In vitro experiment, we used immunofluorescence to detect ROS production, and RT-qPCR to detect gene expression of GPX4, Fpn1, and Ptgs2. Key findings: In vivo, LGZGD improved cardiac systolic function. LGZGD significantly reduced MDA, LDH, and CK levels, increased SOD activity, enhanced the protein expression of Nrf2, GPX4, and Fpn1, and decreased Ptgs2 levels. In vitro, LGZGD-containing serum significantly reduced ROS, increased the gene expression of GPX4 and Fpn1, and decreased the gene expression of Ptgs2. Furthermore, compared with the LGZGD (si-NC) group, the LGZGD (si-Nrf2) group had decreased gene expression of Nrf2, GPX4, and Fpn1 and increased gene expression of Ptgs2. Conclusions: LGZGD can ameliorate DOX-cardiotoxicity by activating the Nrf2 signaling pathway and inhibiting ferroptosis in cardiomyocytes.
MeSH term(s)	Rats ; Animals ; Ferroptosis ; Cyclooxygenase 2 ; NF-E2-Related Factor 2 ; Reactive Oxygen Species ; Doxorubicin/toxicity ; Plant Extracts
Chemical Substances	ling-gui-zhu-gan decoction ; Cyclooxygenase 2 (EC 1.14.99.1) ; NF-E2-Related Factor 2 ; Reactive Oxygen Species ; Doxorubicin (80168379AG) ; Plant Extracts
Language	English
Publishing date	2024-01-19
Publishing country	England
Document type	Journal Article
ZDB-ID	3107-0
ISSN	2042-7158 ; 0022-3573 ; 0373-1022
ISSN (online)	2042-7158
ISSN	0022-3573 ; 0373-1022
DOI	10.1093/jpp/rgae005
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Article ; Online: Ling Zhi-8, a fungal immunomodulatory protein in

Li, Ju-Pi / Chu, Ching-Liang / Chao, Wan-Ru / Yeh, Cheng-Siang / Lee, Yi-Ju / Chen, Dz-Chi / Yang, Shun-Fa / Chao, Yu-Hua

Aging

2023 Volume 15, Issue 9, Page(s) 3621–3634

Abstract: ... for its clinical utility. Ling Zhi-8 (LZ-8), a fungal immunomodulatory protein in ...

Abstract	CPT-11 (Irinotecan) remains an important chemotherapeutic agent against various solid tumors nowadays. Potential adverse effects, especially gastrointestinal toxicities, are the main limiting factor for its clinical utility. Ling Zhi-8 (LZ-8), a fungal immunomodulatory protein in
MeSH term(s)	Mice ; Animals ; Reishi ; Irinotecan ; Claudin-1/genetics
Chemical Substances	Irinotecan (7673326042) ; Claudin-1
Language	English
Publishing date	2023-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.204695
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Article ; Online: Inhibition of estrogen sulfation by Xian-Ling-Gu-Bao capsule.

He, Liangliang / Chen, Chanjuan / Duan, Shuyi / Li, Yang / Li, Chuan / Yao, Xinsheng / Gonzalez, Frank J / Qin, Zifei / Yao, Zhihong

The Journal of steroid biochemistry and molecular biology

2022 Volume 225, Page(s) 106182

Abstract: Xian-Ling-Gu-Bao capsule (XLGB) is a widely prescribed traditional Chinese medicine used ...

Abstract	Xian-Ling-Gu-Bao capsule (XLGB) is a widely prescribed traditional Chinese medicine used for the treatment of osteoporosis. However, it significantly elevates levels of serum estrogens. Here we aimed to assess the dominant contributors of sulfotransferase (SULT) enzymes to the sulfation of estrogens and identify the effective inhibitors of this pathway in XLGB. First, estrone, 17β-estradiol, and estriol underwent sulfation in human liver S9 extracts. Phenotyping reactions and enzyme kinetics assays revealed that SULT1A1, 1A2, 1A3, 1C4, 1E1, and 2A1 all participated in estrogen sulfation, with SULT1E1 and 1A1 as the most important contributors. The incubation system for these two active enzymes were optimized with Tris-HCl buffer, DL-Dithiothreitol (DTT), MgCl
MeSH term(s)	Humans ; Molecular Docking Simulation ; Sulfotransferases/metabolism ; Polyphenols ; Estrogens
Chemical Substances	Sulfotransferases (EC 2.8.2.-) ; Polyphenols ; Estrogens
Language	English
Publishing date	2022-09-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1049188-0
ISSN	1879-1220 ; 0960-0760
ISSN (online)	1879-1220
ISSN	0960-0760
DOI	10.1016/j.jsbmb.2022.106182
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Article ; Online: Ling-Gui-Qi-Hua formula alleviates left ventricular myocardial fibrosis in rats with heart failure with preserved ejection fraction by blocking the transforming growth factor-β1 /Smads signaling pathway.

Shi, Yujiao / Liu, Chunqiu / Xiong, Shuang / Yang, Ling / Yang, Chenguang / Qiao, Wenbo / Liu, Yongcheng / Liu, Siyu / Liu, Jiangang / Dong, Guoju

Journal of ethnopharmacology

2023 Volume 317, Page(s) 116849

Abstract: Ethnopharmacological relevance: Ling-Qui-Qi-Hua (LGQH) decoction, composed of Poria cocos (Schw ... a compound formula derived from Ling-Gui-Zhu-Gan decoction recorded in the Treatise on Febrile and ...

Abstract	Ethnopharmacological relevance: Ling-Qui-Qi-Hua (LGQH) decoction, composed of Poria cocos (Schw.) Wolf, Cinnamomum cassia (L.) J. Presl, Paeonia veitchii Lynch, and Atractylodes macrocephala Koidz., is a compound formula derived from Ling-Gui-Zhu-Gan decoction recorded in the Treatise on Febrile and Miscellaneous. It has shown cardioprotective effects on patients or rats with heart failure with preserved ejection fraction (HFpEF). Nevertheless, the active ingredients of LGQH and its anti-fibrotic mechanism remain unknown. Aim of the study: To determine the active ingredients in LGQH decoction and verify that LGQH decoction may inhibit left ventricular (LV) myocardial fibrosis in HFpEF rats by blocking the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway from the perspective of animal experiments. Materials and methods: First, liquid chromatography-mass spectrometry (LC-MS) technology was used to identify active components in the LGQH decoction. Secondly, a rat model of the metabolic syndrome-associated HFpEF phenotype was established and subsequently received LGQH intervention. The mRNA and protein expression of targets in the TGF-β1/Smads pathway were detected by quantitative real-time polymerase chain reaction and western blot analysis. Finally, molecular docking was conducted to examine the interactions between the active ingredients in the LGQH decoction and key proteins of the TGF-β1/Smads pathways. Results: According to LC-MS analysis, the LGQH decoction contained 13 active ingredients. In animal experiments, LGQH attenuated LV hypertrophy, enlargement, and diastolic function in HEpEF rats. Mechanically, LGQH not only down-regulated TGF-β1, Smad2, Smad3, Smad4, α-SMA, Coll I, and Coll III mRNA expressions and TGF-β1, Smad2, Smad3, P-Smad2/Smad3, Smad4, α-SMA, and Coll I protein expressions, but also up-regulated Smad7 mRNA and protein expressions, which ultimately led to myocardial fibrosis. Furthermore, molecular docking confirmed that 13 active ingredients in the LGQH decoction have excellent binding activities to the critical targets of the TGF-β1/Smads pathway. Conclusion: LGQH is a modified herbal formulation with multiple active ingredients. It might alleviate LV remodeling and diastolic dysfunction and inhibit LV myocardial fibrosis by blocking TGF-β1/Smads pathways in HFpEF rats.
MeSH term(s)	Rats ; Animals ; Transforming Growth Factor beta1/metabolism ; Heart Failure/drug therapy ; Molecular Docking Simulation ; Stroke Volume ; Fibrosis ; Signal Transduction ; Cardiomyopathies/metabolism ; RNA, Messenger/metabolism
Chemical Substances	Transforming Growth Factor beta1 ; RNA, Messenger
Language	English
Publishing date	2023-06-28
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	134511-4
ISSN	1872-7573 ; 0378-8741
ISSN (online)	1872-7573
ISSN	0378-8741
DOI	10.1016/j.jep.2023.116849
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Article ; Online: A novel strategy for the multi-components division and discovering pharmacodynamic material basis of Chinese herbal compounds: A case study of Xian-Ling-Gu-Bao capsule.

Guan, Yuxin / Yang, Bing / Zeng, Jingqi / Mo, Yulin / Wu, Xiaochun / Yang, Yanjun / Feng, Liang / Jia, Xiaobin

Journal of pharmaceutical and biomedical analysis

2024 Volume 243, Page(s) 116112

Abstract: ... the Xian-Ling-Gu-Bao (XLGB) capsule as a case study. Cheminformatics-based components partitioning was ...

Abstract	The therapeutic effects of Chinese herbal compounds are often achieved through the synergistic interactions of multiple ingredients. However, current research predominantly focuses on individual ingredients, neglecting the holistic nature of Chinese herbal compounds. This study proposes a novel strategy to elucidate the pharmacodynamic material basis of Chinese herbal compounds based on their multi-components (components named 'ZuFen' in China, it refers to multiple ingredients with similar chemical structures) composition, using the Xian-Ling-Gu-Bao (XLGB) capsule as a case study. Cheminformatics-based components partitioning was conducted after sourcing ingredients from various databases, resulting in a total of 856 ingredients which were categorized into nine major components. Furthermore, the pharmacodynamic ingredients of XLGB capsule were determined by analyzing the ingredients that were absorbed into the bloodstream. Through a combination of these ingredients and screening for absorption, the Dipsacus asper saponin components, Psoralea corylifolia coumarin components, and Epimedium flavonoid polyglycosides components were isolated. The anti-osteoporosis efficacy of these components were evaluated in zebrafish, demonstrating their capability to reverse mineralization reduction caused by prednisolone. These findings further support the idea that these components serve as the material basis for the pharmacological efficacy of XLGB capsule. This study provides a novel systematic strategy for discovering the pharmacodynamic material basis of the efficacy of Chinese herbal compounds based on a 'multi-components' perspective.
MeSH term(s)	Animals ; Zebrafish ; Drugs, Chinese Herbal/chemistry ; Flavonoids ; Saponins ; Osteoporosis/drug therapy ; Chromatography, High Pressure Liquid/methods
Chemical Substances	Drugs, Chinese Herbal ; Flavonoids ; Saponins
Language	English
Publishing date	2024-03-16
Publishing country	England
Document type	Journal Article
ZDB-ID	604917-5
ISSN	1873-264X ; 0731-7085
ISSN (online)	1873-264X
ISSN	0731-7085
DOI	10.1016/j.jpba.2024.116112
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Article: Comparison of pharmacokinetic profiles of seven major bioactive components in normal and non-alcoholic fatty liver disease (NAFLD) rats after oral administration of Ling-Gui-Zhu-Gan decoction by UPLC-MS/MS.

Nie, Wenlong / Yang, Yang / Li, Ling / Ding, Yue / Chen, Xingmi / Li, Ming / He, Ning / Ji, Guang / Zhang, Yong / Kang, Ping / Zhang, Tong

Frontiers in pharmacology

2023 Volume 14, Page(s) 1174742

Abstract: ... in the plasma of rats after the oral administration of Ling-Gui-Zhu-Gan decoction (LGZGD). Besides, this very ...

Abstract	A sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was hereby developed for the determination of seven components, namely, glycyrrhizic acid, glycyrrhetinic acid, dehydrotumulosic acid, isoliquiritin, liquiritin, atractylenolide III, and cinnamic acid, in the plasma of rats after the oral administration of Ling-Gui-Zhu-Gan decoction (LGZGD). Besides, this very method was methodologically validated for specificity, linearity, inter-day and intra-day precision, accuracy, matrix effect, extraction recovery, and stability. It was also successfully used for the first time to compare the pharmacokinetic characteristics of the seven components after oral administration of LGZGD to normal rats and non-alcoholic fatty liver disease (NAFLD) rats. The results indicated significant differences between the pharmacokinetic characteristics of normal and NAFLD rats. To further reveal the different pharmacokinetic behaviors, the expressions of enzymes and transporters in the liver of normal and NAFLD rats were detected using UPLC-MS/MS. In the NAFLD rats, UDP-glucuronosyltransferase 1-1 (UGT1A1) and nine transporters were significantly inhibited and a positive correlation was observed between them and the AUC of the major components. The present results indicate that the pharmacokinetic differences between the normal and NAFLD rats might be attributed to the significant lower expression levels of both the metabolic enzyme UGT1A1 and nine transporter proteins in the NAFLD rats than in the normal rats. Meanwhile, UGT1A1 and the nine transporter proteins might be used as potential biomarkers to assess the ameliorative effect of LGZGD on NAFLD, which could provide useful information to guide the clinical application of LGZGD.
Language	English
Publishing date	2023-05-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1174742
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Article ; Online: Network pharmacology and experimental validation to investigate the mechanism of Nao-Ling-Su capsule in the treatment of ischemia/reperfusion-induced acute kidney injury.

Lin, Yongqiang / Xu, Lili / Lin, Huibin / Cui, Weiliang / Jiao, Yang / Wang, Bing / Li, Huifen / Wang, Xiaojie / Wu, Jichao

Journal of ethnopharmacology

2024 Volume 326, Page(s) 117958

Abstract: Ethnopharmacological relevance: Nao-Ling-Su Capsule (NLSC) is a traditional prescription, which is ...

Abstract	Ethnopharmacological relevance: Nao-Ling-Su Capsule (NLSC) is a traditional prescription, which is composed of fifteen herbs such as epimedium, Polygala tenuifolia, and Schisandra chinensis. It has the effect of strengthening the brain, calming nerves, and protecting the kidney, which has been used clinically for many years to strengthen the brain and kidney. However, the effect of NLSC in the treatment of acute kidney injury (AKI) is still unclear. Aim of the study: The present study aims to elucidate the pharmacological actions of NLSC in the treatment of AKI. Materials and methods: Molecular targets for NLSC and AKI were obtained from various databases, and then we built networks of interactions between proteins (PPI) by employing string databases. Additionally, we employed the DAVID database to conduct gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking was conducted to analyze the interaction between core components and their corresponding core targets. Next, the C57BL male mice model of ischemia/reperfusion damage (IRI) was developed, and the nephridial protective effect of NLSC was evaluated. The accuracy of the expected targets was confirmed using real-time quantitative polymerase chain reaction (RT-qPCR). The renal protective effect of NLSC was assessed using an immortalized human kidney tubular (HK-2) cell culture produced by oxygen-glucose deprivation (OGD). Results: Network pharmacology analysis identified 199 common targets from NLSC and AKI. STAT3, HSP90AA1, TP53, MAPK3, JUN, JAK2, and VEGFA could serve as potential drug targets and were associated with JAK2/STAT3 signaling pathway, PI3K-Akt signaling pathway, etc. The molecular docking analysis confirmed significant docking activity between the main bioactive components and core targets, including STAT3 and KIM-1. Moreover, the AKI mice model was successfully established and NLSC pretreatment could improve renal function and alleviate renal damage. NLSC could alleviate renal inflammation and tubular cell apoptosis, and decrease the expression of STAT3 and KIM-1 in AKI mice. In vitro, both NLSC and drug-containing serum may protect HK-2 cells by inhibiting STAT3 signaling, especially STAT3-mediated apoptosis and KIM-1 expression. Conclusion: NLSC could alleviate renal inflammation and apoptosis, exerting its beneficial effects by targeting the STAT3/KIM-1 pathway. NLSC is a promising candidate for AKI treatment and provides a new idea and method for the treatment of AKI.
MeSH term(s)	Humans ; Male ; Animals ; Mice ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Network Pharmacology ; Phosphatidylinositol 3-Kinases ; Kidney ; Acute Kidney Injury/drug therapy ; Reperfusion Injury/drug therapy ; Ischemia ; Reperfusion ; Nephritis ; Inflammation ; Drugs, Chinese Herbal/pharmacology ; Drugs, Chinese Herbal/therapeutic use
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Drugs, Chinese Herbal
Language	English
Publishing date	2024-02-22
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	134511-4
ISSN	1872-7573 ; 0378-8741
ISSN (online)	1872-7573
ISSN	0378-8741
DOI	10.1016/j.jep.2024.117958
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Article ; Online: An integrated strategy by absorbed component characterization, pharmacokinetics, and activity evaluation for identification of potential nephroprotective substances in Zhu-Ling decoction.

Shu, Zhi-Heng / Fan, Cai-Lian / Wei, Hong-Yan / Li, Zi-Ting / Norimoto, Hisayoshi / Tang, Xi-Yang / Yao, Zhi-Hong / Yao, Xin-Sheng / Dai, Yi

Journal of separation science

2023 Volume 46, Issue 17, Page(s) e2300331

Abstract: An efficient strategy for the identification of potential nephroprotective substances in Zhu-Ling ... constituents absorbed components in vivo of Zhu-Ling decoction by using ultra-performance liquid chromatography ... activities in hydrogen peroxide-induced Vero cells. As a result, 111 compounds in Zhu-Ling decoction and 36 ...

Abstract	An efficient strategy for the identification of potential nephroprotective substances in Zhu-Ling decoction has been established with the integration of absorbed components characterization, pharmacokinetics, and activity evaluation. A qualitative method was developed to characterize the chemical constituents absorbed components in vivo of Zhu-Ling decoction by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A quantitative method was established and validated for the simultaneous determination of eight compounds in rat plasma by using ultra-performance liquid chromatography-triple quadruple tandem mass spectrometry. Finally, the nephroprotective activities of absorbed components with high exposure were assessed by cell survival rate, superoxide dismutase, and malondialdehyde activities in hydrogen peroxide-induced Vero cells. As a result, 111 compounds in Zhu-Ling decoction and 36 absorbed components were identified in rat plasma and urine, and poricoic acid A, poricoic acid B, alisol A, 16-oxo-alisol A, and dehydro-tumulosic acid had high exposure levels in rat plasma. Finally, poricoic acid B, poricoic acid A, 16-oxo-alisol A, and dehydro-tumulosic acid showed remarkable nephroprotective activity against Vero cells damage induced by hydrogen peroxide. Besides, superoxide dismutase and malondialdehyde activities were obviously regulated in hydrogen peroxide-induced Vero cells by treatment with the four compounds mentioned above. Therefore, these four compounds were considered to be effective substances of Zhu-Ling decoction due to their relatively high exposure in vivo and biological activity. This study provided a chemical basis for the action mechanism of Zhu-Ling decoction in the treatment of chronic kidney diseases.
MeSH term(s)	Chlorocebus aethiops ; Rats ; Animals ; Hydrogen Peroxide ; Vero Cells ; Mass Spectrometry/methods ; Triterpenes ; Drugs, Chinese Herbal/pharmacology ; Drugs, Chinese Herbal/chemistry ; Chromatography, High Pressure Liquid/methods
Chemical Substances	poricoic acid A ; Hydrogen Peroxide (BBX060AN9V) ; Triterpenes ; Drugs, Chinese Herbal
Language	English
Publishing date	2023-07-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2047990-6
ISSN	1615-9314 ; 1615-9306
ISSN (online)	1615-9314
ISSN	1615-9306
DOI	10.1002/jssc.202300331
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Article: LING-GUI-ZHU-GAN DECOCTION ALLEVIATES COGNITIVE DEFICITS IN ALZHEIMER'S DISEASE BY ACTIVATING THE NUCLEAR FACTOR-ERYTHROID FACTOR 2-RELATED FACTOR 2/THE ANTIOXIDANT RESPONSIVE ELEMENT SIGNALING PATHWAY

Zhang, Jingyuan / Yang, Dongqing / Zhao, Juan / Ling, Yun / Zhou, Chunxiang

Current topics in nutraceutical research

2023 Volume 21, Issue 1, Page(s) 1

Language	English
Document type	Article
ZDB-ID	2116319-4
ISSN	1540-7535
Database	Current Contents Nutrition, Environment, Agriculture

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Article ; Online: Chinese herbal formula shen-ling-bai-zhu-san to treat chronic gastritis: Clinical evidence and potential mechanisms.

Jin, Wei / Zhong, Juan / Song, Yang / Li, Ming-Fei / Song, Shi-Yi / Li, Chun-Run / Hou, Wei-Wei / Li, Qing-Jie

World journal of gastroenterology

2022 Volume 28, Issue 33, Page(s) 4890–4908

Abstract: Background: Chronic gastritis (CG) is an inflammatory disease of the gastric mucosa. Shen-ling-bai ...

Abstract	Background: Chronic gastritis (CG) is an inflammatory disease of the gastric mucosa. Shen-ling-bai-zhu san (SLBZS), a traditional Chinese medicine formula, is widely used for treating CG. Nevertheless, its effects are currently unclear. Aim: To determine the clinical evidence and potential mechanisms of SLBZS for the treatment of CG. Methods: We systematically searched 3 English (PubMed, Embase, Medline) and 4 Chinese databases (Cochrane Library Central Register of Controlled Trials, China National Knowledge Infrastructure database, Wanfang Data Knowledge Service Platform, and the VIP information resource integration service platform) without language or publication bias restriction. Qualified studies were selected according to pre-set inclusion and exclusion criteria. RevMan 5.3 software was used for meta-analysis and literature quality assessment, Stata 14.0 software was used for sensitivity analysis, GRADE profiler 3.6 was used to evaluate the quality of evidence. And then, network pharmacology analysis was applied to primary research the mechanisms of action of SLBZS on CG. Results: Fourteen studies were finally included, covering 1335 participants. Meta-analysis indicated that: (1) SLBZS was superior to conventional therapies [risk ratio (RR): 1.29, 95% confidence interval (CI): 1.21 to 1.37, Conclusion: SLBZS might be useful in treating CG, but long-term effects and specific clinical mechanisms of it maintain unclear. More samples and high-quality clinical experiments should be assessed and verified in the next step.
MeSH term(s)	Drugs, Chinese Herbal/adverse effects ; ErbB Receptors ; Gastritis/drug therapy ; Humans ; Language ; Phosphatidylinositol 3-Kinases ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-akt
Chemical Substances	Drugs, Chinese Herbal ; Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2022-06-30
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Systematic Review
ZDB-ID	2185929-2
ISSN	2219-2840 ; 1007-9327
ISSN (online)	2219-2840
ISSN	1007-9327
DOI	10.3748/wjg.v28.i33.4890
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